GABA is an inhibitory amino acid found in the mammalian central nervous system (CNS). It has been reported that dysfunctions with GABA neurotransmission in the CNS may contribute or even cause psychiatric and neurological diseases such as epilepsy, schizophrenia, Parkinson's disease, Huntington's Chorea and dyskinesia (Saletu B., et al., International Journal of Clinical Pharmacology, Therapy, and Toxicology, 1986;24:362-373).
Gabapentin (1-(aminomethyl)-cyclohexaneocetic acid):
was designed as a GABA analog that would cross the blood-brain barrier. Gabapentin was found to have anticonvulsant and antispastic activity with extremely low toxicity in man. Gabapentin is presently marketed under the trademark Neurontin® as adjunctive therapy in the treatment of partial seizures in patients with epilepsy.
U.S. Pat. Nos. 4,024,175 and 4,087,544 disclose the use of gabapentin for the treatment of certain forms of epilepsy, faintness attacks, hypokinesia, and cranial traumas. Additionally, gabapentin brings about an improvement of cerebral functions and thus is useful in treating geriatric patients. U.S. Pat. No. 5,084,479 discloses the use of gabapentin in neurodegenerative disorders. U.S. Pat. No. 5,025,035 discloses the use of gabapentin in treating depression; U.S. Pat. No. 5,510,381 discloses the use of gabapentin in treating mania and bipolar disorders. U.S. Pat. No. 5,792,796 discloses the use of gabapentin in treating anxiety and panic. U.S. Pat. No. 6,127,418 discloses the use of gabapentin in treating gastrointestinal damage; U.S. Pat. Nos. 4,894,476 and 4,960,931 disclose a novel crystalline monohydrate form of gabapentin; and U.S. Pat. Nos. 5,133,451; 5,319,135; 5,362,883; 5,693,845; 5,091,567; and 5,068,413 disclose processes for preparing gabapentin as well as intermediates used in these processes. All of the aforementioned United States Patents are incorporated herein by reference.
Pregabalin ((S)-4-amino-3-(2-methylpropyl)butanoic acid)
is another GABA analog disclosed in U.S. Pat. No. 5,563,175 for the treatment of seizure disorders including epilepsy, which is herein incorporated by reference.
U.S. Pat. No. 6,117,906 discloses the use of pregabalin in treating anxiety; U.S. Pat. No. 6,001,876 discloses the use of pregabalin in treating pain; U.S. Pat. No. 6,127,418 discloses the use of pregabalin in treating gastrointestinal damage; and U.S. Pat. Nos. 5,599,973; 5,608,090; 5,684,189; 5,710,304; 5,616,793; 5,629,447; 5,637,767; 5,840,956; 6,046,353; and 6,028,214 disclose processes for preparing pregabalin as well an intermediate used in these processes. All of the aforementioned United States Patents are incorporated herein by reference.
U.S. Pat. No. 4,024,175 discloses the administration of gabapentin enterally or parenterally within wide dosage ranges in liquid and solid form. Subsequently, it was disclosed in U.S. Pat. No. 6,054,482, which is herein incorporated by reference, that gabapentin was converted to a lactam, i.e., 2-azaspiro[4.5]decan-3-one:
Furthermore, lactam formation unexpectedly occurred in the solid phase and under dry storage conditions. Since the gabapentin lactam displayed a certain toxicity, levels of this compound must be reduced to a minimum for reasons of safety. In further investigations, it was confirmed that liquid formulations of gabapentin undergo cyclization to form lactam much more readily than in the solid state. Additionally, it was discovered that gabapentin has a very bitter taste. Finally, there is a need to administer high doses of gabapentin in the treatment of certain diseases. In some cases, doses of up to 1500 mg per day are given to patients.
In view of the above issues, pharmaceutical compositions of gabapentin have been limited to solid dosage forms, such as capsules and tablets.
Pregabalin, similar to gabapentin, also is prone to cyclization to a lactam, i.e., 4-isobutyl-pyrrolidin-2-one:

Thus, there is a need for a liquid pharmaceutical composition of GABA analogs. In particular, liquid formulations of gabapentin and pregabalin would be desirable for the treatment of small children and elderly patients, since these patient groups require doses of gabapentin or pregabalin which are easy to swallow and which can be individually dosed.
The object of the present invention is a liquid pharmaceutical composition which is amenable to high concentrations of a GABA analog, is stable, has low levels of lactam, and has an agreeable taste.
We have surprisingly and unexpectedly found that a GABA analog can be formulated in a stable liquid pharmaceutical composition having low levels of the GABA analog lactam with a pH of about 5.5 to about 7.0 containing at least one polyhydric alcohol. Additionally, the present composition has an agreeable taste.